On 1^st April 2018, Toujeo (insulin glargine 300 Units/mL) – a once-daily basal insulin was listed on the Pharmaceutical Benefits Scheme for the treatment of diabetes mellitus in adults.^1,2 To understand how this treatment fits into the current paradigm, the limbic spoke with Coffs Harbour Endocrinologist and renowned Diabetes Specialist Dr Sultan Linjawi.

“First of all, it is important to remember that we’re not changing apples for oranges here. The introduction of insulin glargine 300 Units/mL is not a revolution, but it is an important step forward in the evolution of basal insulins when it comes to the risk of hypoglycaemia in type 2 patients. From my perspective, if you have a type 2 patient on a basal insulin – even if they are doing well with their HbA1c – you may want to change to the 300 Units/mL formulation because clinical trial data suggests it is going to give you the same result with a lower risk of hypoglycaemia than 100 Units/mL,” explains Dr Linjawi.²

The goal post shifts yet again^3-5

Up until the 1990s, there was ongoing uncertainty about treatment and glycaemic targets for diabetes mellitus.³ Intensive glycaemic control was emerging as important in reducing the incidence and progression of microvascular complications, however intensive treatment at the time often resulted in hyperinsulinaemia, weight gain and an increase in hypoglycaemia – which were theoretically believed to have adverse effects on macrovascular disease.³

Based on the results of studies like the UK Prospective Diabetes Study (UKPDS) for type 2 diabetes and the Diabetes Control and Complications Trial (DCCT) in type 1, treatment was focussed on more aggressive efforts to lower blood glucose levels to as close to normal as possible.^3-6 “At this point, guidelines were in favour of accepting the short-term risk of hypos for the long-term gain of glycaemic control,” says Dr Linjawi.^3-6 “ Now, there seems to have been a shift back towards hypoglycaemic avoidance. Many studies delivered better glycaemic control based on HbA1c but had higher adverse events for people with diabetes and much of that seemed to be driven by hypoglycaemia. So, the pendulum shifted back. Even now, you see in the way we optimise insulin doses for patients – we give as much as can be tolerated without the patient having a hypo and that’s the best we can do. The question we need to ask is can we find therapies that provide good control with lower (and ultimately none) rates of hypos?”

In with the new

As Dr Linjawi explains, the last step forward in terms of basal insulins was insulin glargine 100 Units/mL. “It had a long duration of action compared with what we were used to, but some patients weren’t controlled with only once daily dosing. Plus, because the injection volume was larger, we were always having to carefully monitor the injection site – simply because so much had to go in there.”⁷

Indeed, Toujeo is the same molecule clinicians have been used to giving patients for many years now (insulin glargine), in a smaller volume.² This gives the once-daily formulation more consistent absorption, which in turn is believed to provide a more consistent effect on glycaemic control than the 100 Units/mL formulation.^2,8

The listing of Toujeo on the PBS is welcomed by Dr Linjawi as he thinks it will be something every clinician will consider in all patients on basal insulins. “Conceptually I can’t see why we will continue using the 100 Units/mL formulation. Even in a type 2 patient who appears well on their current 100 Units/mL therapy, the evidence suggests the risk of a hypo can be reduced. Anything we can do to minimise patients experiencing hypos that can influence them in this way is important. This is where I see the 300 Units/mL formulation fitting into treatment for type 2 patients. It gives us the same confidence of glycaemic control while reducing the risk of the adverse event that patient (and doctors) fear most – hypos in type 2.”

Closing the gap

Insulin glargine 300 Units/mL was examined versus the 100 Units/mL formulation in the EDITION clinical trials. Across the trials, the key primary endpoint for patients was HbA1c change from baseline to endpoint.^9-11 The main secondary efficacy endpoint was the percentage of patients with one or more confirmed (≤3.9 mmol/L) or severe nocturnal (0000-0559 h) hypoglycaemia events.^9-11

• EDITION 1 was a 6-month, multinational, randomised, open-label, parallel group study that examined insulin glargine 300 Units/mL versus 100 Units/mL in patients with type 2 diabetes on a basal bolus regimen. It demonstrated equivalency with respect to HbA1c reduction, with a significantly reduced risk of nocturnal hypoglycaemia and no significant difference for hypoglycaemia at any time of the day.⁹
• EDITION 2 was a 6-month, multicentre, randomised, open-label, two-arm study that examined insulin glargine 300 Units/mL versus 100 Units/mL in patients with type 2 diabetes on basal insulin and oral anti-hyperglycaemic drugs. It demonstrated equivalency with respect to HbA1c reduction, with a significantly reduced risk of nocturnal hypoglycaemia and hypoglycaemia at any time of the day.¹⁰
• EDITION 3 was a 6-month, multicentre, randomised, open-label, parallel group study that examined insulin glargine 300 Units/mL versus 100 Units/mL in insulin-naïve patients with type 2 diabetes on oral anti-hyperglycaemic drugs. It demonstrated equivalency with respect to HbA1c reduction, with a numerically lower risk of nocturnal or anytime of day hypoglycaemia that was not statistically significant.¹¹
• A meta-analysis of the EDITION clinical studies found reductions in HbA1c were sustained over 12 months with 300 Units/mL versus 100 Units/mL, while the risk of confirmed (≤3.9 mmol/L) or severe hypoglycaemia was lower with 300 Units/mL versus 100 Units/mL at night (relative risk 0.85 [95% CI 0.77–0.92]) and 6% lower at any time of day (relative risk 0.94 [95% CI 0.90–0.98]).¹²
• EDITION 4 was a 6-month, multicentre, randomised, four-arm, parallel group, Phase 3a study that examined insulin glargine 300 Units/mL versus 100 Units/mL in patients with type 1 diabetes on a mealtime and basal insulin regimen. It demonstrated equivalency with respect to glucose control, with an equivalent risk of hypoglycaemia.¹³

There was consistent evidence that the 300 Units/mL formulation provided equivalent glycaemic control with a reduced risk of hypoglycaemia for patients with type 2 diabetes.^9-12

This is good news according to Dr Linjawi, but also highlights how current study designs could be limiting progress in the field. The problem with insulin therapy studies, says Dr Linjawi, “is that current study designs are treat-to-target studies – where they are looking at the differences in adverse events (such as hypos) for the same level of diabetes control. They don’t push glycaemic control further than the current standard of care.^9-24 In reality, because of the way we optimise therapies using the maximal tolerated doses, if you could have a treatment that gave you no hypos you would have the ability to achieve perfect glycaemic control. At least with treatments like insulin glargine 300 Units/mL we are a step closer to fewer hypos for our patients with type 2 diabetes.”^8-11

 References:

1. Australian Government. Department of Health. Pharmaceutical Benefits Scheme. Available at: http://www.pbs.gov.au/medicine/item/11302W-11308E-9039R (accessed 2 April 2018).
2. Toujeo (insulin glargine) Approved Product Information, 30 June 2015.
3. K. Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:837–853.
4. Del Prato S et al. Diabetes Care 2009;32(S2):S217-S222.
5. International Diabetes Federation. Global guidelines for type 2 diabetes. Available at http://www.idf.org/home, 2005 (accessed 2 April 2018).
6. Nathan DM et al. Diabetes Care 2014;37:9-16.
7. Lantus (insulin glargine) Approved Product Information, 4 October 2017.
8. Bailey TS et al. Diab Metab 2018;44(1):15-21.
9. Riddle MC et al. Diabetes Care 2014;37:2755-2762.
10. Yki-Jarvinen H et al. Diabetes Care 2014;37(12):3235-3243.
11. Bolli GB et al. Diab Obes Metab 2015;17(4):386-394.
12. Ritzel R et al. Diab Obes Metab 2015;17(9):859-867.
13. Home PD et al. Diabetes Care 2015; org/10.2337/dc15-0249.
14. Bergenstal RM et al. Diabetes Care 2017;40(4):554-560.

This article was sponsored by sanofi-aventis australia Pty Ltd. The content is based on published studies and experts’ opinions, the views expressed are not necessarily those of sanofi-aventis australia Pty Ltd.